FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W1934692007> ?p ?o ?g. }

• W1934692007 abstract "B-Chronic lymphocytic leukemia (B-CLL) is characterized by accumulation of apoptotic resistant CD5+ B lymphocytes. There is an increased secretion of Wnt ligands indicating an autocrine loop leading to the extended survival of B-CLL cells. Lymphoid enhancer factor 1 (LEF-1) is a potent transcription factor regulating the expression of several Wnt induced target genes. A comprehensive gene expression profiling from two independent studies revealed that LEF-1 mRNA was ~3000 fold overexpressed in B-CLL when compared to its healthy counterpart. The objective of this present study is to demonstrate the therapeutic benefit of inhibiting LEF-1 expression in B-CLL cells using novel small molecule inhibitors CGP049090 and PKF115-584 in vivo and in vitro. In order to explore the anti-leukemic potential of CGP049090 and PKF115-584 we tested its effects on freshly isolated B-CLL cells, prolymphocytic cell line (JVM-3 & MEC-1) and in a subcutaneous mouse xenograft model. The present study shows that, in freshly isolated B-CLL cells there was high protein expression and nuclear localization of LEF-1 and β-catenin indicating active LEF-1 mediated transcription whereas LEF-1 remained undetectable in healthy B cells. Preliminary experiments of LEF-1 inhibition using siRNAs resulted in increased apoptosis indicating LEF-1 plays an important role in the survival of B-CLL cells. This observation was extended using CGP049090 and PKF-115584 as they induce dose dependent cytotoxicity in B-CLL, whereas the healthy B cells are not significantly affected. The half maximal inhibitory concentration (IC50) was less than 1 µM in primary B-CLL cells and cell lines whereas it was more than 5 µM in healthy B cells. CGP049090 and PKF-115584 induced apoptotic cell death in primary B-CLL cells and cell lines by cleavage of caspases 8, 9, 3 and 7 and subsequent cleavage of Poly (adenosine diphospate-ribose) polymerase (PARP). Both inhibitors also altered the expression of several anti-apoptotic proteins like X-linked Inhibitor of Apoptosis Protein (XIAP), Mantle cell lymphoma-1 (Mcl-1) and B cell lymphoma-2 (Bcl-2). Co-Immunoprecipitation experiments revealed that both the inhibitors effectively disrupt the β-catenin/LEF-1 interaction, resulting in the down regulation of LEF-1 target genes such c-myc, cyclin D1 and LEF-1. Furthermore, when the inhibitors were tested in an in vivo JVM-3 subcutaneous xenograft nude mouse model, more than 70% inhibition of tumor growth and an increase in the median survival of the treated group without leading to systemic toxicity was observed. Immunohistochemistry analysis of the tumor sections revealed LEF-1 down regulation and subsequent inhibition of proliferation by down regulation of Proliferating Cell Nuclear Antigen (PCNA) and increase in apoptosis (cleaved PARP). In summary, the data showed that LEF-1 is a potential therapeutic target in the treatment of B-CLL. Both CGP049090 and PKF115-584 showed potent inhibitory effects on the survival of CLL cells in vitro and in vivo without affecting the healthy cells. Both CGP049090 and PKF115-584 are hence, potential anti-cancer agents in B-CLL and other neoplastic malignancies with aberrant LEF-1/ T cell factor (TCF) transcriptional activity. Further investigations are warranted to determine the feasibility of these small molecules for therapeutic approach in humans." @default.
• W1934692007 created "2016-06-24" @default.
• W1934692007 creator A5012998953 @default.
• W1934692007 date "2009-01-01" @default.
• W1934692007 modified "2023-09-27" @default.
• W1934692007 title "LEF-1 is a potential therapeutic target in the treatment of Chronic lymphocytic leukemia" @default.
• W1934692007 cites W115350123 @default.
• W1934692007 cites W122353466 @default.
• W1934692007 cites W1243376384 @default.
• W1934692007 cites W1429374962 @default.
• W1934692007 cites W143624314 @default.
• W1934692007 cites W1494249446 @default.
• W1934692007 cites W1499296962 @default.
• W1934692007 cites W1501443642 @default.
• W1934692007 cites W1506229563 @default.
• W1934692007 cites W1527161131 @default.
• W1934692007 cites W154103547 @default.
• W1934692007 cites W1552162287 @default.
• W1934692007 cites W1554815317 @default.
• W1934692007 cites W1564039428 @default.
• W1934692007 cites W1568951543 @default.
• W1934692007 cites W1580962701 @default.
• W1934692007 cites W1605230984 @default.
• W1934692007 cites W1611419331 @default.
• W1934692007 cites W1616028725 @default.
• W1934692007 cites W1635607892 @default.
• W1934692007 cites W1756818535 @default.
• W1934692007 cites W1794964846 @default.
• W1934692007 cites W180295822 @default.
• W1934692007 cites W1836452880 @default.
• W1934692007 cites W1844467096 @default.
• W1934692007 cites W1942856476 @default.
• W1934692007 cites W1963571549 @default.
• W1934692007 cites W1964223564 @default.
• W1934692007 cites W1965829723 @default.
• W1934692007 cites W1965851569 @default.
• W1934692007 cites W196676216 @default.
• W1934692007 cites W1966803171 @default.
• W1934692007 cites W1968366612 @default.
• W1934692007 cites W1969611129 @default.
• W1934692007 cites W1970184435 @default.
• W1934692007 cites W1970584505 @default.
• W1934692007 cites W1973323054 @default.
• W1934692007 cites W1973916894 @default.
• W1934692007 cites W1978768129 @default.
• W1934692007 cites W1979547093 @default.
• W1934692007 cites W1979826746 @default.
• W1934692007 cites W1980955976 @default.
• W1934692007 cites W1981766282 @default.
• W1934692007 cites W1983755269 @default.
• W1934692007 cites W1984975924 @default.
• W1934692007 cites W1985473001 @default.
• W1934692007 cites W1985736574 @default.
• W1934692007 cites W1989194294 @default.
• W1934692007 cites W1991332313 @default.
• W1934692007 cites W1993192840 @default.
• W1934692007 cites W1994116142 @default.
• W1934692007 cites W1994441995 @default.
• W1934692007 cites W1994922837 @default.
• W1934692007 cites W1995133375 @default.
• W1934692007 cites W1995246974 @default.
• W1934692007 cites W2000015384 @default.
• W1934692007 cites W2002331458 @default.
• W1934692007 cites W2002404925 @default.
• W1934692007 cites W2005088732 @default.
• W1934692007 cites W2006777007 @default.
• W1934692007 cites W2007127627 @default.
• W1934692007 cites W2009515759 @default.
• W1934692007 cites W2010235407 @default.
• W1934692007 cites W2010342942 @default.
• W1934692007 cites W2010459522 @default.
• W1934692007 cites W2013209137 @default.
• W1934692007 cites W2014995450 @default.
• W1934692007 cites W2015120596 @default.
• W1934692007 cites W2015890115 @default.
• W1934692007 cites W2016434683 @default.
• W1934692007 cites W2017531120 @default.
• W1934692007 cites W2017668082 @default.
• W1934692007 cites W2019274594 @default.
• W1934692007 cites W2023192965 @default.
• W1934692007 cites W2031192472 @default.
• W1934692007 cites W2032417358 @default.
• W1934692007 cites W2033989981 @default.
• W1934692007 cites W2035192365 @default.
• W1934692007 cites W2036758696 @default.
• W1934692007 cites W2038426029 @default.
• W1934692007 cites W2039079146 @default.
• W1934692007 cites W2040040334 @default.
• W1934692007 cites W2040263952 @default.
• W1934692007 cites W2041675180 @default.
• W1934692007 cites W2043139965 @default.
• W1934692007 cites W2045046145 @default.
• W1934692007 cites W2049090395 @default.
• W1934692007 cites W2052561585 @default.
• W1934692007 cites W2052661123 @default.
• W1934692007 cites W2056524221 @default.
• W1934692007 cites W2057003766 @default.
• W1934692007 cites W2057199920 @default.
• W1934692007 cites W2059743738 @default.
• W1934692007 cites W2061000716 @default.

• next